System and process for purification of astatine-211 from target materials

ABSTRACT

A new column-based purification system and approach are described for rapid separation and purification of the alpha-emitting therapeutic radioisotope  211 At from dissolved cyclotron targets that provide highly reproducible product results with excellent  211 At species distributions and high antibody labeling yields compared with prior art manual extraction results of the prior art that can be expected to enable enhanced production of purified  211 At isotope products suitable for therapeutic medical applications such as treatment of cancer in human patients.

FEDERALLY-SPONSORED RESEARCH AND DEVELOPMENT

This invention was made with Government support under ContractDE-AC05-76RL01830 awarded by the U.S. Department of Energy. TheGovernment has certain rights in the invention.

CLAIM TO PRIORITY

This application claims priority from provisional U.S. PatentApplication No. 62/487,290 filed 29 Apr. 2017. The contents of which areincorporated herein in their entirety.

FIELD OF THE INVENTION

The present invention relates generally to radionuclide separationsystems and processes and more particularly to a system and process forenhanced purification of Astatine 211 (²¹¹At) from target materials foruse in medical applications.

BACKGROUND OF THE INVENTION

²¹¹At is a promising therapeutic isotope for use in medical applicationsincluding treatment of cancers in humans such as lymphoma and leukemia.While still in the clinical trials stage, the demand for this isotopecan be expected to rise dramatically. Presently, there are nocommercially available fully automated systems and approaches availableto provide this valuable radioisotope in a highly purified andstandardized form for use in these various medical applications. Whileexisting methods such as liquid/liquid extraction approaches exist, thismanual approach that is labor intensive, dose-intensive and timeconsuming. These factors coupled to the fact that ²¹¹At also has ahalf-life of only ˜7 h renders such an arrangement of limitedapplication.

Another approach known in the art for preparation of the ²¹¹At isotopeis a furnace distillation process that volatilizes ²¹¹At from anirradiated bismuth (Bi) target obtained from a cyclotron. However, hightemperatures needed to volatilize the ²¹¹At from the target oftenresults in some volatilization of Bi from the target which contaminatesthe recovered ²¹¹At resulting in an unpurified product. This approachhas also been shown to work best on low-mass Bi targets raising concernsthat these low-mass Bi targets may not be suitable for scaling needed togenerate hundreds of mCi of ²¹¹At for near-term clinical trials andbeyond. Additionally, production of a gaseous ²¹¹At product raises otherradiological protection concerns given the potential for catastrophicrelease of the gaseous radionuclide into either the work space orrelease from a stack should the furnace assembly rupture during ²¹¹Atdistillation.

While various attempts have been made in arriving at a column based oreven automated process for obtaining ²¹¹At, the PEG column method asproposed by Wilbur et.al in US Patent Pub No. 2016/0053345 simply hasnot demonstrated efficacy or operability. See A. L. Wooten, M.-K. Chyan,et al., “PEG column studies designed to eliminate nitric aciddistillation in automation of the wet chemistry approach to isolation ofastatine-211”, 16th International Workshop on Targetry and TargetChemistry, Santa Fe, NM, AIP Conference Proceedings (2016). “While thatresult was encouraging, only ˜13% of the captured ²¹¹At was removed fromthe PEG column with the use of concentrated NH₄OH as the eluent. Giventhese drawbacks in the prior art, a continuing need exists for new andeffective ²¹¹At purification process.” The present invention is asignificant advance in this direction.

Additional advantages and novel features of the present disclosure willbe set forth as follows and will be readily apparent from thedescriptions and demonstrations set forth herein. Accordingly, thefollowing descriptions of the present disclosure should be seen asillustrative of the disclosure and not as limiting in any way.

SUMMARY

The present disclosure provides examples of systems and methods for theseparation of ²¹¹At from dissolved cyclotron targets using small columnswith preselected flow rates to achieve the separation in minutes. Aswill be described hereafter, these embodiments provide (1) lowerprocessing complexity compared to the prior art with fewer and simplerprocess steps; (2) reduced preparation time for purified ²¹¹At productfractions for clinical uses and applications compared to the prior artextraction approach; (3) automated capabilities allowing remote handlingand processing in shielded environments thus reducing radiation doses topersonnel stemming from handling and contact; (4) purified productfractions in a low elution volume enabling rapid removal of the liquidvolume for transport of the purified ²¹¹At product, for example, as asalt; (5) a ²¹¹At product of superior purity and consistent quality; (6)a purified ²¹¹At product with a superior distribution of a preferredspecies of isotope; and (7) a purified product with a comparable orbetter antibody labeling efficiency that can be expected to beadvantageous for medical and therapeutic applications.

In one example, a dissolved sample containing ²¹¹At is loaded on to acolumn wherein the desired ²¹¹At materials are then captured. The columnis then washed and the resulting ²¹¹At materials are then eluted fromthe column using specified materials and conditions. Specifically in oneexample, a method for producing a purified ²¹¹At isotope product isdescribed wherein a dissolved cyclotron target solution containing ²¹¹Atisotopes is passed through a separation device including a column withpreselected packing material to recover ²¹¹At isotopes from thedissolved target solution included within. In some instances thecaptured ²¹¹At isotope is later eluted from the preselected packingmaterial and captured in a collection device. In some instances, thedissolved target solution includes Bi nitrate salts and ²¹¹At dissolvedin an acid such as hydrochloric acid (HCl) solution. A conditioningsolution and/or a wash solution can also be utilized before or after theloading on the column to enhance the capture and/or recovery ofmaterials from the column. In one example, the pre-selected packingmaterial within the column is a macroporous polymer resin.

This can all be performed using a fluidic system that includes a targetsolution containing bismuth salts and ²¹¹At isotopes dissolved in anacid and tubing operatively connected to separation column through avalve so as to enable delivery of the target solution to the separationcolumn at a preselected flow rate. In use the target solution is passedthrough the separation column and ²¹¹At isotopes are collected on apacking material within the separation column.

In one particular set of examples a clinically useful single dose amountof ²¹¹At was obtained using only 20 mL to load the target on the column,8 mL to wash the column, and then eluted in ˜2 mL while retaining 88% ofactivity as compared to ˜78% average for other method such as the methodset forth in the article “Evaluation of a Wet Chemistry Method forIsolation of Cyclotron Produced [²¹¹At] Astatine” by Balkin et. al.,Appl. Sci. 2013, 3(3), 636-655; doi:10.3390/app3030636 referred to attimes as the Wilbur method, after the corresponding author on the paper.

Isolated ²¹¹At samples obtained from the method described in the presentapplication used ‘next day’ had >70% labeling efficiency using aCA10-B10 antibody, thus supporting the desired aim of a process capableof producing a pure product at a high yield with a consistent qualityand purity, and suitable labeling properties. Such a process can beautomated to minimize need for sample contact by personnel with theassociated radiation doses and enable reduced processing time. Thisprocess eliminates a need for complicated and multi-step manualprocessing steps; minimizes waste products; and addresses otherdrawbacks and limitations imposed by manual processing systems.

The purpose of the foregoing abstract is to enable the United StatesPatent and Trademark Office and the public generally, especially thescientists, engineers, and practitioners in the art who are not familiarwith patent or legal terms or phraseology, to quickly determine thenature and essence of the technical disclosure of the application. Theabstract is neither intended to define the invention of the applicationwhich is measured by the claims nor is it intended to be limiting as tothe scope of the invention in any way.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows one embodiment of a system of the present invention forautomated isolation of an ²¹¹At isotope product.

FIG. 2 shows a second embodiment of a system of the present inventionfor the automated isolation of an ²¹¹At isotope product.

FIGS. 3(a)-3(c) show column effluent activity fractions for ²¹¹At duringtarget load/wash/²¹¹At elute steps, presented as the ²¹¹At isolationprocess performed across three cyclotron bombarded and dissolved Bitargets.

DETAILED DESCRIPTION

The present disclosure provides examples and descriptions of enhancedpurification and chemical isolation of ²¹¹At for medical and therapeuticapplications such as diagnosis and treatment of cancer in patients. Inmany of these examples purification using a separation column with asmall internal volume as low as ˜0.25 cc provides substantiallyquantitative extraction of ²¹¹At from dissolved cyclotron targets atselected flow rates. These separation columns can be packed, forexample, with an uncoated material containing a macroporous polymericresin such as AMBERCHROM® CG-71s that is sandwiched in the column, forexample, between two acid-resistant frits.

Various examples and embodiments of specific disclosures are providedhereafter and described in the attached drawings. Referring first toFIG. 1, a separation system and approach for production of a purifiedradioisotope ²¹¹At product from dissolved cyclotron targets fortherapeutic applications is shown and described. Referring first to FIG.1, in this system, a vessel 8 containing a dissolved bismuth targetsolution 100, for example, in an acid that contains the desired ²¹¹Atisotope to be obtained is connected by tubing 24 to a fluid distributionvalve 14 such as a multiple flow path distribution valve which is alsoconnected by tubing to various other features of the device such as theseparation column 10, as well as vessels 8 that contain solutions (100,200, 300, 400). A syringe pump 12 coupled to distribution valve 14 isconfigured to deliver solutions (100, 200, 300, 400) at selected flowrates to a separation column 10 filled with a selected packing material30. From this column 10 solutions are passed by tubing past a detector16 and on to a fraction collector 18. In other embodiments such as theconfiguration of FIG. 2, multiple pumps (12, 12′) and valves (14, 14′)can be included. In addition a gate valve 26 that separates product fromwaste can be included instead of or in addition to the detector 16 andcollector 18 shown in FIG. 1. The entire operation can be controlled bya computer 20.

In this approach, the bismuth target is dissolved in nitric acid of aselected molar concentration to form a target solution 100 containingdissolved bismuth ions and dissolved ²¹¹At isotope ions. In another stepnitric acid in the solution containing the dissolved Bi isotope ions and²¹¹At isotope ions is subsequently removed, for example, by distillingthe dissolved target solution that forms stable nitrate salts of boththe Bi and ²¹¹At isotopes. Next, these Bi and ²¹¹At nitrate salts areredissolved in hydrochloric (HCl) acid solution at a selected molarconcentration and introduced to the containment vessel 8 filled withprepared dissolved target solution 100 for column separation. The targetsolution 100 is then passed through the separation column 10 packed witha selected packing material such as, e.g., macroporous CG-71 polymerresin or another suitable material at a preselected flow rate toseparate the ²¹¹At isotope ions from the dissolved bismuth targetsolution. Separated ²¹¹At isotope ions are retained on the packingmaterial in the separation column 10 and the ²¹¹At depleted bismuthtarget solution passes from the column for subsequent collection asshown in FIG. 1 or waste as shown in FIG. 2.

In one instance, the process operates by conditioning the system bypassing an acidic conditioning solution 200 through the system toestablish the desired acidity and loading conditions and enhance theloading of the ²¹¹At ions in the target solution on to the column. Next,a target solution 100 containing ²¹¹At dissolved in a Bi target is addedto the system and loaded on to the columns 10. (In some instances asmall volume of air can be dispensed into the column influent line toremove the remaining conditioning fluid present in the system prior toloading.) Once loaded on to the columns the materials can be allowed torest for a period of time and then washed using an acidic wash solution300. (In some instances the conditioning solution and the wash solutionare the same) The ²¹¹At is then eluted from the column using a eluentsolution 400 from whence the target material can be processed forclinical delivery.

In one example system and process were used in an example whereinconditioning took place by passing 5 mL of 8M HCl at a flow rate lessthan or equal to 2 ml/min, followed by passing a small volume of airthrough the lines. After passing the air through the lines, 15-20 mL ofa target solution containing ²¹¹At dissolved in a Bi target was added tothe system at a low rate less than or equal to 2 mL/min loaded on to thecolumns.

In this instance the target solution contained a Bi mass between 3.5 and6 g which had been dissolved using HNO₃, in this process the HNO₃ wasthen distilled away and the remaining salts re dissolved in 8M HCl. Thisbismuth target dissolution can be performed by an automated process suchas the one described by O'Hara et al in article entitled “An automatedflow system incorporating in-line acid dissolution of bismuth metal froma cyclotron irradiated target assembly for use in the isolation ofastatine-211”, Applied Radiation and Isotopes 122 (2017) 202-210. Thecontents of which are herein incorporated by reference. This system fora distillation assembly and a process for dissolving the resultingbismuth nitrate salt to form the target solution are described therein.Such a system can also be functionally interconnected with the systemssuch as those shown in FIG. 1 or 2 to form a complete automated systemfor separations. While these methods and systems are described forforming the target solution it is to be distinctly understood that theimplementation is not limited thereto but may be variously alternativelyembodied, according to the needs and necessities of a user.

After the loading sequence 8 mL of 8M HCl was then used as a washsolution and passed through the system at a flow rate of less than orequal to 2 mL/min. An eluent solution consisting of 8 mL of 10M HNO₃ wasthen passed through the system at flow rate of 1 mL/min to elute theisolated ²¹¹At from the column. A resulting ²¹¹At product fraction,examples of which are shown in FIGS. 3(a)-3(c) were isolated in about1.5 mL.

Testing of the eluted ²¹¹At demonstrated that while chemical yields werehigh, preferably greater than or equal to about 70%, more particularlygreater than or equal to about 90%, and yet more particularly greaterthan or equal to about 95%. The present invention also recovers ²¹¹Ations from the column at recovery yields greater than or equal to about95%. The present invention also reduces process complexity enablingsignificantly shorter processing times as low as 20 minutes or bettercompared with the generally longer processing times (up to 3× greater)of the prior art solvent extraction process. Automated processingprovided by the present invention also reduces radiation doses topersonnel stemming from sample contact and handling that is notaddressed in the manual solvent extraction process described above.

In other alternative embodiments and configurations such as the example,shown in FIG. 2 a pair of syringe pumps and distribution valves are usedwith one pump and valve utilized, for example, for column conditioning,washing, and eluting with the other pump and valve utilized, forexample, for handling the dissolved target. Packing material in theseparation column recovers and retains the ²¹¹At isotope from thedissolved target solution on the column packing material until the ²¹¹Atisotope is eluted from the column. In the preferred embodiment, packingmaterial utilized for separation, recovery, and purification of the²¹¹At isotope from the dissolved bismuth target is a macroporouspolymeric resin such as AMBERCHROM CG-71s or another suitable packingmaterial. An optional detector, such as a radiochromatography detectorcapable of monitoring ²¹¹At activity in column effluents, can be coupledto the separation column.

In some embodiments the radiochromatography detector is a NaI(TI)scintillation detector. Other detectors may also be utilized. Anoptional fraction collector is shown coupled to the detector forcollection of column effluents. In this embodiment the system alsoincludes a control computer for automated control of system componentsas well as separation process parameters such as, for example,distribution valve flow channel and syringe pump delivery volumes aswell as dissolved target and eluent flow rates. Control of other systemcomponents and processing parameters are also envisioned.

As described above exemplary tests utilized a flow rate ≤2.0 mL/min butfaster or slower flow rates may be utilized and are thus not intended tobe limited. The separation column can also be pre-conditioned in apreparatory step with a small volume(s) of hydrochloric acid (HCl). Inaddition, clean HCl solution can be introduced to the column to wash anyresidual traces of target solution from the column yielding a highlypurified ²¹¹At product prior to the elution step. ²¹¹At product elutionprofiles are controlled in part utilizing higher or lower HNO₃concentrations and are thus not intended to be limited. In one example,10 M HNO₃ was utilized to efficiently remove sorbed ²¹¹At isotope ionsfrom the column. Eluted ²¹¹At product solutions can then be neutralizedwith a small quantity of strong base (NaOH) to create a solution havinga desired pH, preferably a nearly neutral or neutral solution.

In one set of tests, one embodiment of the automated fluidic systemdescribed above was utilized and operated to process a full-scale Bitarget containing ˜14 mCi ²¹¹At. The column utilized a resin bed ofdimensions ˜5.7 mm dia.×˜11.3 mm tall. Packing material in theseparation column was a macroporous, polymeric resin (e.g., AMBERCHROMCG-71 ROHM and HAAS utilized conventionally to separate biomoleculesincluding proteins, peptides, and nucleic acids) of a generally smallparticle size, preferably at or below about 120 microns (μm), morepreferably at or below about 75 μm, and most preferably at or belowabout 35 μm. Other packing materials are also envisioned. The packingmaterial for separation and purification of the ²¹¹At isotope waspositioned within the column sandwiched between two acid-resistant fritssuch as glass fiber frits or polymer (e.g., polyethylene) frits. ²¹¹Atactivity in all column effluents was monitored utilizing a NaI(TI)scintillation radiochromatography detector. Column effluents werecollected as fractions of known volume in a fraction collector. Table 1shows the information related to various Bi target masses and theactivity of the ²¹¹At in each of the outlined cyclotron bombardedtargets.

TABLE 1 Run ²¹¹At Activity, Date Bi Target Mass, g mCi (EOB) Dec. 8,2016 4.54 13.2 Feb. 1, 2017 5.54 26.8 Apr. 5, 2017 3.29 24.0

In another set of experiments a Bi target irradiated in a cyclotroncontaining ˜25-30 mCi ²¹¹At was dissolved in 10 M HNO₃ for a totalvolume of 15.5 mL. 50% (7.75 mL) of the solution was removed as aduplicate sample and replaced with 7.75 mL of 2.2 g non-irradiated Bimetal separately dissolved in 10 M HNO₃ so as to provide ˜100% of theoriginal Bi and original volume of HNO₃ found in the originallydissolved target. HNO₃ was distilled from the solution in a distillationchamber leaving a salt cake of Bi nitrate salts. These salts wereredissolved in 8 M HCl to yield a final solution volume of 18.75 mL(0.242 g Bi/mL). The sample container containing the final solution(4.54 g dissolved Bi and ˜3.2 mCi²¹¹At) was connected to the fluiddelivery system and processed. A second cyclotron target sample with5.54 g Bi metal containing ˜27 mCi ²¹¹At was also dissolved andprocessed. A third sample containing 3.29 g Bi metal containing about24mCi ²¹¹At was also dissolved and processed.

FIGS. 3A-3C show column separation profiles for ²¹¹At products resultingfrom replicate purification runs obtained from separate cyclotronirradiated Bi targets. Asterisks (*) in these figures represent volumesof the ²¹¹At product fractions of between 1.5 and 2.0 mL selected forsubsequent species distribution and antibody labelling tests. Thesevolumes are not intended to be limiting.

Column effluent volumes are shown (FIGS. 3A-3C) during which thedissolved target loading, column washing, and column eluting steps wereperformed. During column elution, ²¹¹At elution profiles were tracedwith the radiochromatography detector so that the fraction collectorcould collect the purified ²¹¹At isotopes in a minimum volume. Singlepeaks in these figures correspond to ²¹¹At product fractions recoveredfor subsequent speciation distribution and antibody labeling tests.Volumes of individual ²¹¹At fractions were analyzed by dose calibrator.Percent activity for each fraction was calculated by taking eachfraction volume and dividing by the total activity recovered in theprocess (column effluent fractions+activity remaining on thecolumn+activity remaining in the vessel that originally contained thedissolved target+activity in waste vessels). Table 2 lists results forthe purification approach and ²¹¹At activity results obtained in eachstep of the purification process for the 13 mCi, 27 mCi, and 24 mCi²¹¹At target samples, respectively.

TABLE 2 Dec. 8, 2016 Column Feb. 1, 2017 Column Apr. 5, 2017 ColumnEffluent Recoveries Effluent Recoveries Effluent Recoveries Activity,Activity Activity, Activity Activity, Activity Step mCi Distribution, %mCi Distribution, % mCi Distribution, % Col. Condition — — — — DissolvedTarget 0.144 1.1 0.062 0.2 0.040 0.2 Load Col. Wash 0.0283 0.2 0.011 0.00.010 0.0 Elute 12.601 95.5^(b) 25.7 96.1^(c) 22.950 95.6^(d) Residue on0.420 3.2 0.622 2.3 0.564 2.3 Column Misc. waste 0.728 2.7 0.439 1.8streams Target Total 13.2 100 26.8 102 24.0 101 a. Activities reportedfor end-of-bombardment (EOB) ^(b)Activity in all elute fractions; theisolated ²¹¹At fraction used for antibody labeling contained 88.4% ofthe target activity in 1.56 mL ^(c)Activity in all elute fractions; theisolated ²¹¹At fraction used for antibody labeling contained 88.5% ofthe target activity in 1.96 mL ^(d)Activity in all elute fractions; theisolated ²¹¹At fraction used for antibody labeling contained 84.4% ofthe target activity in 1.64 mL

Results in Table 2 show that of the total 13.2 mCi, 27 mCi, and 24 mCi²¹¹At obtained from the three targets and loaded onto the columns (atend-of-bombardment, EOB), ˜96% of the total activity was collectedduring column elution. Isolated product fractions were also collected ina small volume (1.56 mL, 1.96 mL, and 1.64 mL) with two containing ˜88%and one containing about 84% of the total ²¹¹At activity. Only 1.1%activity was lost to the column during the loading and washing steps.And only ˜2-3% activity remained in the column resin bed or frits after²¹¹At elution. In this exemplary approach, the column-based methodinvention yields highly purified ²¹¹At that is released in a low volumeacidic product fraction (e.g., 10 M HNO₃). By comparison, the prior artmanual extraction method as set out in the Balking publication has ageneral yield distribution of 78±11%.

Two characteristic astatine peaks appear in the HPLC chromatograms fromHPLC assays which are labeled as peak 1 and peak 2. Astatine Peak 1behaves like iodate and is thus referred to as “astatate”. Astatine Peak2 behaves like iodide and is thus referred to as “astatide”. Maximumtolerance for Peak 1 in the prior art approach is 15%. Peak 2 is apreferred species for establishing antibody labeling efficacy. Minimumthreshold quantity of this species obtained in any purified ²¹¹Atproduct fraction in the prior art approach generally must be greaterthan or equal to 85%. Table 3 shows that purified ²¹¹At productfractions of the present invention are substantially comprised of thepreferred efficacious “astatide” species easily surpassing thresholdquality metrics established for the prior art L/L extraction approach.

TABLE 3 Peak 1 Peak 2 Processing UW ²¹¹At (“astatate”), % (“astatide”),% Date Product Criteria ≤15 ≥85 Dec. 8, 2016 Column Product 6 94 (pH~13) Feb. 1, 2017 Column Product 8 92 (pH ~13) Column Product 2 98 (pH~6.5, after acid swing) Column Product 0.1 99.9 (after taken to saltsand brought to pH ~6.5)^(a) Apr. 5, 2017 Column Product 4.5 95.5 (pH~14) Column Product 12.7 87.3 (after taken to salts and brought to pH~6.5) (solution reconstituted in 50% the original vol.)^(a) *²¹¹Atsolution reconstituted in phosphate buffered saline; has twice thedissolved solids concentration as it had originally

In another set of tests, labeling efficiency of purified ²¹¹At isotopesobtained by the present invention to boron-10 (B-10) conjugated CA10antibodies was determined. ²¹¹At nitrate salts generated by the presentinvention were dissolved in a phosphate buffered saline (PBS) solution.²¹¹At labeling measurements onto the B-10 conjugated CA10 antibodieswere collected for each of the two separate column-generated ²¹¹Atproduct fractions in duplicate using two 0.5 mL aliquots or 1.0 mLaliquots of phosphate buffered saline (PBS)-dissolved ²¹¹At solution.Table 4 lists antibody labeling results for each of the 13.2 mCi, 27mCi, and 24 mCi ²¹¹At column-generated samples performed in at leastduplicate.

TABLE 4 Product Vol. Mass of Processing Labeled, Antibody, Date SamplemL Mg Labeling Yield, % Dec. 8, 2016 A^(a) 0.5 0.5 76.3 B^(a) 0.5 0.573.4 Feb. 1, 2017 A^(b) 1.0 1.0 83.8 B^(c) 1.0 1.0 80.7 Apr. 5, 2017A^(b) 0.5 1.0 82.6 B^(b) 0.5 0.2 79.5 C^(c) 0.5 1.0 77.3 ^(a)Replicatelabeling experiments occurred the next day; performed onpost-neutralized ²¹¹At product ^(b)Post-neutralization of ²¹¹At product^(c)Post-neutralization, evaporation to dryness, and reconstituted inphosphate buffered saline

Slightly lower labeling yields were obtained for the 13 mCi samples asthey were performed a day following ²¹¹At isolation. Yet, results werestill comparable to fresh ²¹¹At product results obtained utilizing theprior art manual extraction method. Results demonstrate that purified²¹¹At products of the present invention exhibit comparable to betterlabeling efficiencies compared to the prior manual extraction method. Inaddition to the sample examples provided in additional embodiments theuse of a PD-10 size exclusion column served as an effective means toremove nitrate salts from the labeling fluid during the step whereinprotein is separated prior to patient injection. FIG. 3 shows columneffluent activity fractions for ²¹¹At during target load/wash/²¹¹Atelute steps. Asterisks indicate single ²¹¹At product fraction that wasisolated for ²¹¹At speciation monitoring by HPLC, ²¹¹At antibodylabeling, and Bi metal contamination. Table 5 shows results from PD-10size exclusion separation of ²¹¹At labeled CA10-B10 antibody fromlabeling solvent for labeling experiments A and C from the final Apr. 5,2017 run which contained about 24 mCi of ²¹¹At. Table 6 shows theResidual Bi contamination in column-generated ²¹¹At product fractions asdetermined by inductively coupled plasma—mass spectrometry analysis of²¹¹At product fraction. The 2/1 run was not as good as the 4/5 run. Thisis because the 2/1 run used the single pump set-up from FIG. 1 and the4/5 run used the dual pump set-up from FIG. 2.

TABLE 5 Antibody- ²¹¹At Nitrate Antibody- ²¹¹At Nitrate bearingActivity, conc., bearing Activity, conc., Fraction μCi^(a) μg/mL^(b)Fraction μCi^(a) μg/mL^(b) A5 181 <0.2 C5 313 <0.2 A6 850 <0.2 C6 995<0.2 A7 1077 <0.2 C7 1088 <0.2 A8 561 <0.2 C8 369 <0.2 A9 78 <0.2 C9 40<0.2 A10 18 <0.2 C10 12 <0.2 ^(a)At end of beam (EOB) ^(b)Values arebelow the reported limit of quantification (LOQ) of the instrument

TABLE 6 ²¹¹At Total Bi in Product Bi Product Bi Processing Fractioncontamination, Fraction, Decontamination Date Vol, mL^(b) μg/mL μgFactor^(e) Feb. 1, 2017 1.96 42.1^(c) 65.7 8.43 × 10⁴ Apr. 5, 2017 1.649.6^(d) 15.7 2.10 × 10⁵ ^(a)As determined by ICP-MS analysis of ²¹¹Atproduct fraction ^(b)From Table 4 ^(c)Results obtained on process thatutilized only a single syringe pump to deliver dissolved Bi target andperform column condition/wash/elute steps (FIG. 1) ^(d)Results obtainedon a process that utilized a separate syringe pump to deliver dissolvedBi target, and one to perform column condition/wash/elute steps (FIG. 2)^(e)Based on ratio of initial Bi mass in bombarded target (see Table 3)to the Bi mass in the ²¹¹At product fraction (column 4, this table)

This data shows that despite the fact that the ²¹¹At/antibody labelingsolution contained multi-molar nitrate concentration (originally fromthe 10M HNO3 ²¹¹At column eluent that required neutralization with NaOH(thereby creating a solution of 10M NaNO3), the size exclusionseparation process prevented the high nitrate levels from passingthrough the PD-10 column and into the final isolated ²¹¹At-labeledprotein fractions.

In some embodiments, purified ²¹¹At isotopes in the nearly neutral orneutral product solutions are directly labeled with the selectedantibody. In some embodiments, liquid from the solution is removed, forexample, in a centrifugal evaporator system to create a ²¹¹At productsalt (e.g., nitrate salt) that stabilizes the ²¹¹At isotopes fortransport for end use in clinical and medical applications. In anotherembodiment, nitrate in the solution can first be decomposed to form analternate salt such as a chloride salt or a hydroxide salt fortransport.

The present application makes clear that the system and method of thepresent invention provides several advantages over the prior art. Thepresent invention (1) has a lower processing complexity compared to theprior art with fewer and simpler process steps; (2) reduces preparationtime for purified ²¹¹At product fractions for clinical uses andapplications compared to the prior art extraction approach; (3) isautomated allowing remote handling and processing in shieldedenvironments thus reducing radiation doses to personnel stemming fromhandling and contact; (4) provides purified product fractions in a lowelution volume enabling rapid removal of the liquid volume for transportof the purified ²¹¹At product, for example, as a salt; (5) provides a²¹¹At product of superior purity and consistent quality; (6) provides apurified ²¹¹At product with a superior distribution of a preferredspecies of isotope; and (7) provides a purified product with acomparable or better antibody labeling efficiency that can be expectedto be advantageous for medical and therapeutic applications.

While a number of embodiments of the present invention have been shownand described, it will be apparent to those skilled in the art that manychanges and modifications may be made without departing from theinvention in its broader aspects. The appended claims are thereforeintended to cover all such changes and modifications that fall withinthe scope of the invention.

What is claimed is:
 1. A method for producing a purified ²¹¹At isotopeproduct, comprising the steps of: passing a dissolved target solutioncomprising ²¹¹At isotopes and Bi nitrate salts dissolved in an acidsolution through a separation column containing a non-PEG packingmaterial to recover ²¹¹At isotopes from the dissolved target solution;and eluting ²¹¹At isotopes from the preselected packing material.
 2. Themethod of claim 1 wherein the acid solution comprises hydrochloric (HCl)acid.
 3. The method of claim 1 further comprising the step of washingthe column with a wash solution prior to eluting.
 4. The method of claim3 wherein the wash solution is an acid solution.
 5. The method of claim4 further comprising the step of conditioning the separation device bypassing an acidic conditioning solution through the system prior topassing the dissolved target solution through the system.
 6. The methodof claim 5 wherein the wash solution and the conditioning solution areHCl solutions.
 7. The method of claim 1 wherein the step of eluting isperformed using nitric acid.
 8. The method of claim 7 wherein the nitricacid has a molarity between 7.5M and 15.8M.
 9. The method of claim 1wherein the dissolved target solution contains Bi and ²¹¹At salts formedby dissolving bismuth target in nitric acid of a selected molarconcentration to form a solution containing dissolved bismuth ions anddissolved ²¹¹At isotope ions and removing the nitric acid from thatsolution to form stable nitrate salts, and dissolving those salts in aHCl solution.
 10. The method of claim 1 wherein the non-PEG packingmaterial is a macroporous polymer resin.
 11. A method for producing apurified ²¹¹At isotope product, comprising the steps of: conditioning asystem comprising at least one sample column containing a preselectedpacking material with an acidic conditioning solution to establish apreselected acidity and loading condition; passing a target solutioncontaining ²¹¹At and Bi salts dissolved in an acid through the column;washing the column with an acid wash solution; and eluting the ²¹¹Atfrom the column using an acidic eluent solution.
 12. The method of claim11 wherein acidic conditioning solution and the acid wash solution arethe same solution.
 13. The method of claim 12 wherein the solution isHCl.
 14. The method of claim 13 wherein the target solution contains²¹¹At and Bi nitrate salts
 15. The method of claim 14 wherein the ²¹¹Atand Bi nitrate salts are dissolved in HCl.
 16. The method of claim 11wherein the conditioning solution was 8M HCl passed through the columnat a flow rate less than or equal to 2 ml/min.
 17. The method of claim11 wherein a volume of the target solution greater than the volume ofthe acid wash solution is added to the system at a flow rate less thanor equal to 2 mL/min to load the column.
 18. A separation system forproducing a purified radioisotope ²¹¹At product from dissolved cyclotrontargets for therapeutic applications comprising: a target solutioncontaining bismuth salts and ²¹¹At isotopes dissolved in an acid, tubingoperatively connected to separation column through a valve so as toenable delivery of the target solution to the separation column at apreselected flow rate, whereby the target solution is passed through theseparation column and ²¹¹At isotopes are collected on a packing materialwithin the separation column as the target solution flows through thecolumn; and an acidic elution solution that is passed over the column toremove the collected ²¹¹At from the column.